Substituted 5-fluoro-1H-pyrazolopyridines and their use

ABSTRACT

The present application relates to novel substituted 5-fluoro-1H-pyrazolopyridines, to processes for their preparation, to their use alone or in combinations for the treatment and/or prophylaxis of diseases, and to their use for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular disorders.

The present application relates to novel substituted5-fluoro-1H-pyrazolopyridines, to processes for their preparation, totheir use alone or in combinations for the treatment and/or prophylaxisof diseases, and to their use for producing medicaments for thetreatment and/or prophylaxis of diseases, in particular for thetreatment and/or prophylaxis of cardiovascular disorders.

One of the most important cellular transmission systems in mammaliancells is cyclic guanosine monophosphate (cGMP). Together with nitrogenmonoxide (NO), which is released from the endothelium and transmitshormonal and mechanical signals, it forms the NO/cGMP system. Guanylatecyclases catalyze the biosynthesis of cGMP from guanosine triphosphate(GTP). The known representatives of this family can be classified bothaccording to structural features and according to the type of ligandsinto two groups: the particulate guanylate cyclases which can bestimulated by natriuretic peptides, and the soluble guanylate cyclaseswhich can be stimulated by NO. The soluble guanylate cyclases consist oftwo subunits and very probably contain one haem per heterodimer, whichis part of the regulatory site. It is of central importance for theactivation mechanism. NO is able to bind to the iron atom of haem andthus markedly increase the activity of the enzyme. Haem-freepreparations cannot, by contrast, be stimulated by NO. Carbon monoxide(CO) is also able to attach to the central iron atom of haem, but thestimulation by CO is distinctly less than that by NO.

By forming cGMP, and owing to the resulting regulation ofphosphodiesterases, ion channels and protein kinases, guanylate cyclaseplays an important role in various physiological processes, inparticular in the relaxation and proliferation of smooth muscle cells,in platelet aggregation and platelet adhesion and in neuronal signaltransmission, and also in disorders which are based on a disturbance ofthe abovementioned processes. Under pathophysiological conditions, theNO/cGMP system may be suppressed, which may lead for example to highblood pressure, platelet activation, increased cellular proliferation,endothelial dysfunction, atherosclerosis, angina pectoris, heartfailure, myocardial infarction, thromboses, stroke and sexualdysfunction.

Owing to the expected high efficiency and few side effects, a treatmentof such disorders which targets the influence of the cGMP signal path inorganisms and is NO-independent is a promising approach.

Hitherto, for the therapeutic stimulation of the soluble guanylatecyclase use has exclusively been made of compounds such as organicnitrates whose effect is based on NO. This is formed by bioconversionand activates soluble guanylate cyclase by attack at the central ironatom of haem. In addition to the side effects, the development oftolerance is one of the decisive disadvantages of this type oftreatment.

In recent years, some substances have been described which stimulatesoluble guanylate cyclase directly, i.e. without prior release of NO,such as, for example 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole[YC-1; Wu et al., Blood 84 (1994), 4226; Mülsch et al., Brit. J.Pharmacol. 120 (1997), 681], fatty acids [Goldberg et al., J. Biol.Chem. 252 (1977), 1279], diphenyliodonium hexafluorophosphate [Pettiboneet al., Eur. J. Pharmacol. 116 (1985), 307], isoliquiritigenin [Yu etal., Brit. J. Pharmacol. 114 (1995), 1587] and various substitutedpyrazole derivatives (WO 98/16223).

WO 00/06569 discloses fused pyrazole derivatives and WO 03/095451carbamate-substituted 3-pyrimidinylyrazolopyridines as stimulators ofsoluble guanylate cyclase.

It is an object of the present invention to provide novel substanceswhich act as stimulators of soluble guanylate cyclase and which have anidentical or improved therapeutic profile compared to compounds knownfrom the prior art, such as, for example, with respect to their in vivoproperties such as, for example, their pharmacokinetic andpharmacodynamic behaviour and/or their dose-activity relationship.

The present invention provides compounds of the general formula (I)

in which

Rhu 1 represents hydrogen or (C₁-C₄)-alkyl, where (C₁-C₄)-alkyl may besubstituted by one or two substituents independently of one anotherselected from the group consisting of fluorine and trifluoromethyl, andtheir N-oxides, salts, solvates, salts of the N-oxides and solvates ofthe N-oxides and salts.

Compounds according to the invention are the compounds of the formula(I) and the N-oxides, salts, solvates and solvates of the N-oxides andsalts thereof, the compounds, encompassed by formula (I), of theformulae specified hereinafter and the N-oxides, salts, solvates andsolvates of the N-oxides and salts thereof, and the compoundsencompassed by formula (I) and specified hereinafter as working examplesand the N-oxides, salts, solvates and solvates of the N-oxides and saltsthereof, to the extent that the compounds encompassed by formula (I) andspecified hereinafter are not already N-oxides, salts, solvates andsolvates of the N-oxides and salts.

In the context of the present invention, preferred salts arephysiologically acceptable salts of the compounds according to theinvention. Also encompassed are salts which are not themselves suitablefor pharmaceutical applications but can be used, for example, forisolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to theinvention include acid addition salts of mineral acids, carboxylic acidsand sulphonic acids, for example salts of hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methanesulphonic acid,ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid,naphthalenedisulphonic acid, formic acid, acetic acid, trifluoroaceticacid, propionic acid, lactic acid, tartaric acid, malic acid, citricacid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to theinvention also include salts of conventional bases, by way of exampleand with preference alkali metal salts (e.g. sodium and potassiumsalts), alkaline earth metal salts (e.g. calcium and magnesium salts)and ammonium salts derived from ammonia or organic amines having 1 to 16carbon atoms, by way of example and with preference ethylamine,diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine,arginine, lysine, ethylenediamine and N-methylpiperidine.

In the context of the invention, solvates refer to those forms of thecompounds according to the invention which, in the solid or liquidstate, form a complex by coordination with solvent molecules. Hydratesare a specific form of the solvates in which the coordination is withwater. Preferred solvates in the context of the present invention arehydrates.

Depending on their structure, the compounds according to the inventionmay exist in different stereoisomeric forms, i.e. in the form ofconfigurational isomers or if appropriate also as conformational isomers(enantiomers and/or diastereomers, including those in the case ofatropisomers). The present invention therefore encompasses theenantiomers or diastereomers and the respective mixtures thereof. Thestereoisomerically uniform constituents can be isolated from suchmixtures of enantiomers and/or diastereomers in a known manner;chromatography processes are preferably used for this, in particularHPLC chromatography on an achiral or chiral phase.

Where the compounds according to the invention can occur in tautomericforms, the present invention encompasses all the tautomeric forms.

The present invention also encompasses all suitable isotopic variants ofthe compounds according to the invention. An isotopic variant of acompound according to the invention is understood here to mean acompound in which at least one atom within the compound according to theinvention compound has been exchanged for another atom of the sameatomic number, but with a different atomic mass than the atomic masswhich usually or predominantly occurs in nature. Examples of isotopeswhich can be incorporated into a compound according to the invention arethose of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur,fluorine, chlorine, bromine and iodine, such as ²H (deuterium), ³H(tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F,³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I. Particular isotopic variants of acompound according to the invention, especially those in which one ormore radioactive isotopes have been incorporated, may be beneficial, forexample, for the examination of the mechanism of action or of the activecompound distribution in the body; due to comparatively easypreparability and detectability, especially compounds labelled with ³Hor ¹⁴C isotopes are suitable for this purpose. In addition, theincorporation of isotopes, for example of deuterium, can lead toparticular therapeutic benefits as a consequence of greater metabolicstability of the compound, for example an extension of the half-life inthe body or a reduction in the active dose required; such modificationsof the compounds according to the invention may therefore in some casesalso constitute a preferred embodiment of the present invention.Isotopic variants of the compounds according to the invention can beprepared by processes known to those skilled in the art, for example bythe methods described below and the methods described in the workingexamples, by using corresponding isotopic modifications of theparticular reagents and/or starting compounds therein.

Moreover, the present invention also encompasses prodrugs of thecompounds according to the invention. Here, the term “prodrugs” refersto compounds which for their part can be biologically active orinactive, but are converted (for example metabolically orhydrolytically) into compounds according to the invention during theirdwell time in the body.

In the context of the present invention, unless specified otherwise, thesubstituents are defined as follows:

In the context of the invention, alkyl represents a straight-chain orbranched alkyl radical having 1 to 4 carbon atoms. The following may bementioned by way of example and by way of preference: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl.

In the context of the invention, halogen represents fluorine, chlorine,bromine and iodine.

If radicals in the compounds according to the invention are substituted,the radicals may be mono- or polysubstituted, unless specifiedotherwise. In the context of the present invention, all radicals whichoccur more than once are defined independently of one another.Substitution by one, two or three identical or different substituents ispreferred.

In the context of the present invention, preference is given tocompounds of the formula (I) in which

R¹ represents hydrogen or methyl, where methyl may be substituted by atrifluoromethyl substituent, and their salts, solvates and solvates ofthe salts.

In the context of the present invention, particular preference is givento the following compounds of the formula (I):

methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate

methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}(2,2,2-trifluoroethyl)carbamate

methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatehydrochloride

methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatesulphate

methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatephosphate

methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatemesylate

methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateethane-1,2-disulphonate

methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatemaleate

methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatenitrate

The individual radical definitions specified in the respectivecombinations or preferred combinations of radicals are, independently ofthe respective combinations of the radicals specified, also replaced asdesired by radical definitions of other combinations.

Particular preference is given to combinations of two or more of thepreferred ranges mentioned above.

The invention further provides a process for preparing the compounds ofthe formula (I) according to the invention, characterized in that thecompound of the formula (II)

[A] is reacted in an inert solvent in the presence of hexabutyltin and asuitable palladium catalyst with intermediate formation of a tin specieswith the compound of the formula (III)

to give the compound of the formula (IV)

this is then reduced in an inert solvent with a suitable reducing agentto give the compound of the formula (V)

and this is then reacted in the presence of a suitable base in thepresence or absence of a solvent with methyl chloroformate to give thecompound of the formula (I-A)

or

[B] the compound of the formula (II) is reacted in an inert solvent withcopper cyanide to give the compound of the formula (VI)

this is then, under acidic conditions, converted into the compound ofthe formula (VII)

this is subsequently reacted in an inert solvent in the presence of asuitable base with the compound of the formula (VIII)

to give the compound of the formula (IX)

and this is then reduced in an inert solvent in the presence of asuitable reducing agent to give the compound (V), and this issubsequently reacted further according to process [A] to give compound(I-A),or

[C] the compound of the formula (I-A) is reacted in an inert solvent inthe presence of a suitable base with a compound of the formula (X)

R^(1A)-X¹ _((X)),

in whichR^(1A) a represents (C₁-C₄)-alkyl, where (C₁-C₄)-alkyl may besubstituted by one or two substituents independently of one anotherselected from the group consisting of fluorine and trifluoromethyl, and

X¹ represents a leaving group such as, for example, halogen, inparticular bromine or iodine, trichloromethanesulphonate, mesylate ortosylate to give a compound of the formula (I-B)

in which R^(1A) has the meaning given above, and the resulting compoundsof the formulae (I-A) and (I-B) are, where appropriate, converted withthe appropriate (i) solvents and/or (ii) acids or bases into theirsolvates, salts and/or solvates of the salts.

Inert solvents for process step (II)+(III)→(IV) are, for example,alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanolor tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane or mineral oilfractions, or other solvents such as dimethylformamide (DMF), dimethylsulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), dimethylacetamide,N-methylpyrrolidone (NMP), pyridine, acetonitrile, sulpholane or elsewater. It is equally possible to use mixtures of the solvents mentioned.Preference is given to dioxane.

Suitable palladium catalysts for process step (II)+(III)→(IV) are, forexample, palladium on activated carbon, palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) chloride,bis(acetonitrile)palladium(II) chloride and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)/dichloromethanecomplex, if appropriate in combination with additional phosphane ligandssuch as, for example, (2-biphenyl)di-tert-butylphosphine,dicyclohexyl[2′,4′,6′-tris(1-methylethyl)biphenyl-2-yl]phosphane(XPHOS), bis(2-phenylphosphinophenyl) ether (DPEphos) or4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) [cf., forexample, Hassan J. et al., Chem. Rev. 102, 1359-1469 (2002)]. Preferenceis given to using tetrakis(triphenylphosphine)palladium(0).

The reaction (II)+(III)→(IV) is generally carried out in a temperaturerange of from +20° C. to +180° C., prepferably from +50° C. to +120° C.,if appropriate in a microwave. The reaction can be carried out atatmospheric, elevated or reduced pressure (for example from 0.5 to 5bar). The reaction is generally carried out at atmospheric pressure.

The reductions (IV)→(V) and (IX)→(V) are carried out in the presence ofa suitable catalyst in an inert solvent in a temperature range of from+20° C. to +40° C. under hydrogen of atmospheric pressure.

Inert solvents for the reductions (IV)→(V) and (IX)→(V) are, forexample, alcohols such as methanol, ethanol, n-propanol, isopropanol,n-butanol or tert-butanol, ethers such as diethyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethylether, or other solvents such as dimethylformamide (DMF), dimethylsulphoxide (DMSO), 1V,N′-dimethylpropyleneurea (DMPU),N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water. It isequally possible to use mixtures of the solvents mentioned. Preferenceis given to DMF and pyridine.

Suitable catalysts for the reactions (IV)→(V) and (IX)→(V) are, forexample, palladium on activated carbon, platinum on carbon, palladiumhydroxide or Raney nickel.

Alternatively, the reductions (IV)→(V) and (IX)→(V) can be carried outusing a metal or metal salt such as, for example, iron, zinc or tin(II)chloride in a suitable acid such as, for example, hydrogenchloride/hydrochloric acid, sulphuric acid, phosphoric acid or aceticacid in a temperature range of from +20° C. to +140° C.

Inert solvents for process step (V)→(I-A) are, for example, alcoholssuch as methanol, ethanol, n-propanol, isopropanol, n-butanol ortert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, halogenatedhydrocarbons such as dichloromethane, trichloromethane, carbontetrachloride, trichloroethylene or chlorobenzene, hydrocarbons such asbenzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions,or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide(DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP),acetonitrile or else water. It is equally possible to use mixtures ofthe solvents mentioned. Preference is given to dimethylformamide andtoluene and also to a mixture of dimethylformamide and toluene.

Suitable bases for the process step (V)→(I-A) are alkali metal hydridessuch as sodium hydride, alkali metal hydroxides such as, for example,lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metalcarbonates such as lithium carbonate, sodium carbonate, potassiumcarbonate or caesium carbonate, alkali metal bicarbonates such as sodiumbicarbonate or potassium bicarbonate, alkali metal alkoxides such assodium methoxide or potassium methoxide, sodium ethoxide or potassiumethoxide or potassium tert-butoxide, or organic amines such astriethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given to pyridine.

The reaction (V)→(I-A) is generally carried out in a temperature rangeof from −10° C. to +30° C., preferably from 0° C. to +20° C. Thereaction can be carried out at atmospheric, elevated or reduced pressure(for example from 0.5 to 5 bar). The reaction is generally carried outat atmospheric pressure.

Inert solvents for process step (II)→(VI) are, for example, ethers suchas diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether ordiethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene,toluene, hexane, cyclohexane or mineral oil fractions, or other solventssuch as dimethylformamide (DMF), dimethyl sulphoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridineor acetonitrile. It is equally possible to use mixtures of the solventsmentioned. Preference is given to DMSO.

The reaction (II)→(VI) is generally carried out in a temperature rangeof from +20° C. to +180° C., preferably from +100° C. to +160° C., ifappropriate in a microwave. The reaction can be carried out atatmospheric, elevated or reduced pressure (for example from 0.5 to 5bar). The reaction is generally carried out at atmospheric pressure.

The reaction (VI)→(VII) is carried out using methods known to the personskilled in the art in a two-step process initially with formation of theimino ester using sodium methoxide in methanol at from 0° C. to +40° C.and subsequent nucleophilic addition of an ammonia equivalent such as,for example, ammonia or ammonium chloride in acetic acid with formationof the amidine (VII) at from +50 to +150° C.

Inert solvents for process step (VII)+(VIII)→(IX) are alcohols such asmethanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol,ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethylether or diethylene glycol dimethyl ether, hydrocarbons such as benzene,xylene, toluene, hexane, cyclohexane or mineral oil fractions, or othersolvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine,acetonitrile or else water. It is equally possible to use mixtures ofthe solvents mentioned. Preference is given to DMF.

Suitable bases for the process step (VII)+(VIII)→(IX) are alkali metalhydroxides such as, for example, lithium hydroxide, sodium hydroxide orpotassium hydroxide, alkali metal carbonates such as lithium carbonate,sodium carbonate, potassium carbonate or caesium carbonate, alkali metalbicarbonates such as sodium bicarbonate or potassium bicarbonate, alkalimetal alkoxides such as sodium methoxide or potassium methoxide, sodiumethoxide or potassium ethoxide or potassium tert-butoxide, or organicamines such as triethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given totriethylamine.

The reaction (VII)+(VIII)→(IX) is generally carried out in a temperaturerange of from +20° C. to +150° C., preferably from +80° C. to +120° C.,if appropriate in a microwave. The reaction can be carried out atatmospheric, elevated or reduced pressure (for example from 0.5 to 5bar). The reaction is generally carried out at atmospheric pressure.

The compound of the formula (VIII) can be prepared analogously to theliterature L. F. Cavalieri, J. F. Tanker, A. Bendich, J. Am. Chem. Soc.,1949, 71, 533.

Inert solvents for the reaction (I-A)→(I-B) are, for example,halogenated hydrocarbons such as dichloromethane, trichloromethane,carbon tetrachloride, trichloroethylene or chlorobenzene, ethers such asdiethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether ordiethylene glycol dimethyl ether, or other solvents such asdimethylformamide (DMF), dimethyl sulphoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridineor acetonitrile. Preference is given to tetrahydrofuran.

Suitable bases for the process step (I-A)→(I-B) are alkali metalhydrides such as potassium hydride or sodium hydride, alkali metalcarbonates such as lithium carbonate, sodium carbonate, potassiumcarbonate or caesium carbonate, alkali metal bicarbonates such as sodiumbicarbonate or potassium bicarbonate, alkali metal alkoxides such assodium methoxide or potassium methoxide, sodium ethoxide or potassiumethoxide or potassium tert-butoxide, amides such as sodium amide,lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide orpotassium bis(trimethylsilyl)amide or lithium diisopropylamide,organometallic compounds such as butyllithium or phenyllithium, ororganic amines such as triethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given to lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and sodiumhydride.

The reaction (I-A)→(I-B) is generally carried out in a temperature rangeof from −78° C. to +40° C., preferably from 0° C. to +20° C. Thereaction can be carried out at atmospheric, elevated or reduced pressure(for example from 0.5 to 5 bar). The reaction is generally carried outat atmospheric pressure.

The preparation processes described can be illustrated in an exemplarymanner by the synthesis schemes below (Schemes 1 to 3):

The compound of the formula (II) can be prepared by cyclizing thecompound of the formula (X)

in an inert solvent with hydrazine hydrate to give the compound of theformula (XI)

then reacting this compound in an inert solvent in the presence of asuitable Lewis acid initially with isopentyl nitrite to give thecorresponding diazonium salt and then converting this salt directly withsodium iodide into the compound of the formula (XII)

and then reacting this compound in an inert solvent in the presence of asuitable base with the compound of the formula (XIII)

Inert solvents for process step (X)→(XI) are alcohols such as methanol,ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or1,2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane or mineral oilfractions, or other solvents such as dimethylformamide (DMF), dimethylsulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU),N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water. It isequally possible to use mixtures of the solvents mentioned.1,2-Ethanediol is preferred.

The reaction (X) (XI) is generally carried out in a temperature range offrom +60° C. to +200° C., preferably from +120° C. to +180° C. Thereaction can be carried out at atmospheric, elevated or reduced pressure(for example from 0.5 to 5 bar). The reaction is generally carried outat atmospheric pressure.

Inert solvents for the reaction (XI)→(XII) are, for example, halogenatedhydrocarbons such as dichloromethane, trichloromethane, carbontetrachloride, trichloroethylene or chlorobenzene, ethers such asdiethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether ordiethylene glycol dimethyl ether, or other solvents such asdimethylformamide (DMF), dimethyl sulphoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridineor acetonitrile. Preference is given to DMF.

Suitable Lewis acids for the process step (XI)→(XII) are borontrifluoride/diethyl ether complex, cerium(IV) ammonium nitrate (CAN),tin(II) chloride, lithium perchlorate, zinc(II) chloride, indium(III)chloride or indium(III) bromide. Preference is given to borontrifluoride/diethyl ether complex.

The reaction (XI)→(XII) is generally carried out in a temperature rangeof from −78° C. to +40° C., preferably from 0° C. to +20° C. Thereaction can be carried out at atmospheric, elevated or reduced pressure(for example from 0.5 to 5 bar). The reaction is generally carried outat atmospheric pressure.

Inert solvents for the reaction (XII)+(XIII)→(II) are, for example,halogenated hydrocarbons such as dichloromethane, trichloromethane,carbon tetrachloride, trichloroethylene or chlorobenzene, ethers such asdiethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether ordiethylene glycol dimethyl ether, or other solvents such asdimethylformamide (DMF), dimethyl sulphoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridineor acetonitrile. Preference is given to DMF.

Suitable bases for the process step (XII)+(XIII)→(II) are alkali metalhydrides such as potassium hydride or sodium hydride, alkali metalcarbonates such as lithium carbonate, sodium carbonate, potassiumcarbonate or caesium carbonate, alkali metal bicarbonates such as sodiumbicarbonate or potassium bicarbonate, alkali metal alkoxides such assodium methoxide or potassium methoxide, sodium ethoxide or potassiumethoxide or potassium tert-butoxide, amides such as sodium amide,lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide orpotassium bis(trimethylsilyl)amide or lithium diisopropylamide,organometallic compounds such as butyllithium or phenyllithium, ororganic amines such as triethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given to caesiumcarbonate.

The reaction (XII)+(XIII)→(II) is generally carried out in a temperaturerange of from 0° C. to +60° C., preferably from +10° C. to +25° C. Thereaction can be carried out at atmospheric, elevated or reduced pressure(for example from 0.5 to 5 bar). The reaction is generally carried outat atmospheric pressure.

The preparation process described can be illustrated in an exemplarymanner by the synthesis scheme below (Scheme 4):

The present invention furthermore provides the compound:5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine

The present invention furthermore provides the compound:5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine

The compounds of the formulae (III) and (XIII) are commerciallyavailable, known from the literature or can be prepared in analogy toliterature processes.

The compound of the formula (X) is known from the literature [cf., forexample, Winn M., J. Med. Chem. 1993, 36, 2676-7688; EP 634 413-A1; CN1613849-A; EP 1626045-A1; WO 2009/018415] and can be prepared in analogyto literature processses or as shown in the synthesis scheme below(Scheme 5):

The compounds according to the invention act as stimulators of solubleguanylate cyclase and have an identical or improved therapeutic profilecompared to compounds known from the prior art, such as, for example,with respect to their in vivo properties such as, for example, theirpharmacokinetic and pharmacodynamic behaviour and/or their dose-activityrelationship and/or their safety profile. They are therefore suitablefor the treatment and/or prophylaxis of diseases in man and animals.

The compounds according to the invention lead to vasorelaxation, to aninhibition of platelet aggregation and to a reduction in blood pressure,and also to an increase in coronary blood flow.

These effects are mediated via direct stimulation of soluble guanylatecyclase and intracellular cGMP increase. Moreover, the compoundsaccording to the invention enhance the effect of substances increasingthe cGMP concentration, such as, for example, EDRF (endothelium-derivedrelaxing factor), NO donors, protoporphyrin IX, arachidonic acid orphenylhydrazine derivatives.

The compounds according to the invention are suitable for the treatmentand/or prophylaxis of cardiovascular, pulmonary, thromboembolic andfibrotic disorders.

Accordingly, the compounds according to the invention can be used inmedicaments for the treatment and/or prophylaxis of cardiovasculardisorders such as, for example, hypertension, acute and chronic heartfailure, coronary heart disease, stable and unstable angina pectoris,peripheral and cardiac vascular disorders, arrhythmias, atrial andventricular arrhythmias and impaired conduction such as, for example,atrioventricular blocks degrees I-III (AB block I-III), supraventriculartachyarrhythmia, atrial fibrillation, atrial flutter, ventricularfibrillation, ventricular flutter, ventricular tachyarrhythmia, Torsadede pointes tachycardia, atrial and ventricular extrasystoles,AV-junctional extrasystoles, Sick-Sinus syndrome, syncopes, AV-nodalre-entry tachycardia, Wolff-Parkinson-White syndrome, of acute coronarysyndrome (ACS), autoimmune cardiac disorders (pericarditis,endocarditis, valvolitis, aortitis, cardiomyopathies), shock such ascardiogenic shock, septic shock and anaphylactic shock, aneurysms, boxercardiomyopathy (premature ventricular contraction (PVC)), for thetreatment and/or prophylaxis of thromboembolic disorders and ischaemiassuch as myocardial ischaemia, myocardial infarction, stroke, cardiachypertrophy, transient and ischaemic attacks, preeclampsia, inflammatorycardiovascular disorders, spasms of the coronary arteries and peripheralarteries, oedema formation such as, for example, pulmonary oedema,cerebral oedema, renal oedema or oedema caused by heart failure,peripheral circulatory disturbances, reperfusion damage, arterial andvenous thromboses, microalbuminuria, myocardial insufficiency,endothelial dsfunction, to prevent restenoses, for example afterthrombolysis therapies, percutaneous transluminal angioplasties (PTA),transluminal coronary angioplasties (PTCA), heart transplants and bypassoperations, and also micro- and macrovascular damage (vasculitis),increased levels of fibrinogen and of low-density lipoprotein (LDL) andincreased concentrations of plasminogen activator inhibitor 1 (PAI-1),and also for the treatment and/or prophylaxis of erectile dysfunctionand female sexual dysfunction.

In the context of the present invention, the term heart failure alsoincludes more specific or related types of disease, such as acutedecompensated heart failure, right heart failure, left heart failure,global failure, ischaemic cardiomyopathy, dilated cardiomyopathy,hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heartdefects, heart valve defects, heart failure associated with heart valvedefects, mitral stenosis, mitral insufficiency, aortic stenosis, aorticinsufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonaryvalve stenosis, pulmonary valve insufficiency, combined heart valvedefects, myocardial inflammation (myocarditis), chronic myocarditis,acute myocarditis, viral myocarditis, diabetic heart failure, alcoholiccardiomyopathy, cardiac storage disorders, and diastolic and systolicheart failure.

In addition, the compounds according to the invention can also be usedfor the treatment and/or prophylaxis of arteriosclerosis, impaired lipidmetabolism, hypolipoproteinaemias, dyslipidaemias,hypertriglyceridaemias, hyperlipidaemias, hypercholesterolaemias,abetalipoproteinaemias, sitosterolaemia, xanthomatosis, Tangier disease,adipositas, obesity and of combined hyperlipidaemias and metabolicsyndrome.

The compounds according to the invention can additionally be used forthe treatment and/or prophylaxis of primary and secondary Raynaud'sphenomenon, of microcirculation impairments, claudication, peripheraland autonomic neuropathies, diabetic microangiopathies, diabeticretinopathy, diabetic ulcers on the extremities, gangrene, CRESTsyndrome, erythematosis, onychomycosis, rheumatic disorders and forpromoting wound healing.

The compounds according to the invention are furthermore suitable fortreating urological disorders such as, for example, benign prostatesyndrome (BPS), benign prostate hyperplasia (BPH), benign prostateenlargement (BPE), bladder outlet obstruction (BOO), lower urinary tractsyndromes (LUTS, including Feline Urological Syndrome (FUS)), disordersof the urogenital system including neurogenic over-active bladder (OAB)and (IC), incontinence (UI) such as, for example, mixed urinaryincontinence, urge urinary incontinence, stress urinary incontinence oroverflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, benignand malignant disorders of the organs of the male and femal urogenitalsystem.

The compounds according to the invention are furthermore suitable forthe treatment and/or prophylaxis of kidney disorders, in particular ofacute and chronic renal insufficiency and acute and chronic renalfailure. In the context of the present invention, the term renalinsufficiency comprises both acute and chronic manifestations thereof,as well as underlying or related kidney diseases such as renalhypoperfusion, intradialytic hypotension, obstructive uropathy,glomerulopathies, glomerulonephritis, acute glomerulonephritis,glomerulosclerosis, tubulointerstitial diseases, nephropathic diseasessuch as primary and congenital kidney disease, nephritis, immunologicalkidney diseases such as kidney graft rejection and immunocomplex-inducedkidney diseases, nephropathy induced by toxic substances, nephropathyinduced by contrast agents, diabetic and non-diabetic nephropathy,pyelonephritis, renal cysts, nephrosclerosis, hypertensivenephrosclerosis and nephrotic syndrome, which can be characterizeddiagnostically for example by abnormally reduced creatinine and/or waterexcretion, abnormally raised blood concentrations of urea, nitrogen,potassium and/or creatinine, altered activity of renal enzymes such as,for example, glutamyl synthetase, altered urine osmolarity or urinevolume, increased microalbuminurea, macroalbuminurea, laesions onglomerulae and arterioles, tubular dilatation, hyperphosphataemia and/orneed for dialysis. The present invention also comprises the use of thecompounds according to the invention for the treatment and/orprophylaxis of sequelae of renal insufficiency, for example pulmonaryoedema, heart failure, uraemia, anaemia, electrolyte disturbances (forexample hypercalaemia, hyponatraemia) and disturbances in bone andcarbohydrate metabolism.

Furthermore, the compounds according to the invention are also suitablefor the treatment and/or prophylaxis of asthmatic disorders, pulmonaryarterial hypertension (PAH) and other forms of pulmonary hypertension(PH) including left-heart disease, HIV, sickle cell anaemia,thromboembolisms (CTEPH), sarkoidosis, COPD or pulmonaryfibrosis-associated pulmonary hypertension, chronic-obstructivepulmonary disease (COPD), acute respiratory distress syndrome (ARDS),acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD),pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysemainduced by cigarette smoke) and cystic fibrosis (CF).

The compounds described in the present invention also represent activecompounds for controlling central nervous system diseases characterizedby disturbances of the NO/cGMP system. They are suitable in particularfor improving perception, concentration, learning or memory aftercognitive impairments like those occurring in particular in associationwith situations/diseases/syndromes such as mild cognitive impairment,age-associated learning and memory impairments, age-associated memorylosses, vascular dementia, craniocerebral trauma, stroke, dementiaoccurring after strokes (post stroke dementia), post-traumaticcraniocerebral trauma, general concentration impairments, concentrationimpairments in children with learning and memory problems,

Alzheimer's disease, Lewy body dementia, dementia with degeneration ofthe frontal lobes including Pick's syndrome, Parkinson's disease,progressive nuclear palsy, dementia with corticobasal degeneration,amyolateral sclerosis (ALS), Huntington's disease, demyelination,multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia,HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. Theyare also suitable for the treatment and/or prophylaxis of centralnervous system disorders such as states of anxiety, tension anddepression, CNS-related sexual dysfunctions and sleep disturbances, andfor controlling pathological disturbances of the intake of food,stimulants and addictive substances.

The compounds according to the invention are furthermore also suitablefor controlling cerebral blood flow and thus represent effective agentsfor controlling migraine. They are also suitable for the prophylaxis andcontrol of sequelae of cerebral infarct (Apoplexia cerebri) such asstroke, cerebral ischaemias and skull-brain trauma. The compoundsaccording to the invention can likewise be employed for controllingstates of pain and tinnitus.

In addition, the compounds according to the invention haveantiinflammatory action and can therefore be used as antiinflammatoryagents for the treatment and/or prophylaxis of sepsis (SIRS), multipleorgan failure (MODS, MOF), inflammatory disorders of the kidney, chronicintestinal inflammations (IBD, Crohn's disease, UC), pancreatitis,peritonitis, rheumatoid disorders, inflammatory skin diseases andinflammatory eye diseases.

Furthermore, the compounds according to the invention can also be usedfor the treatment and/or prophylaxis of autoimmune diseases.

The compounds according to the invention are furthermore suitable forthe treatment and/or prophylaxis of fibrotic disorders of the internalorgans such as, for example, the lung, the heart, the kidney, the bonemarrow and in particular the liver, and also dermatological fibroses andfibrotic eye disorders. In the context of the present invention, theterm fibrotic disorders includes in particular the following terms:hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis,endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitialrenal fibrosis, fibrotic damage resulting from diabetes, bone marrowfibrosis and similar fibrotic disorders, scleroderma, morphea, keloids,hypertrophic scarring (also following surgical procedures), naevi,diabetic retinopathy, proliferative vitreoretinopathy and disorders ofthe connective tissue (for example sarcoidosis).

The compounds according to the invention are furthermore suitable forcontrolling postoperative scarring, for example as a result of glaucomaoperations.

The compounds according to the invention can also be used cosmeticallyfor ageing and keratinized skin.

Moreover, the compounds according to the invention are suitable for thetreatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis,glaucoma and gastroparesis.

The present invention further provides for the use of the compoundsaccording to the invention for the treatment and/or prophylaxis ofdisorders, in particular the disorders mentioned above.

The present invention further provides the use of the compoundsaccording to the invention for the treatment and/or prophylaxis of heartfailure, angina pectoris, hypertension, pulmonary hypertension,ischaemias, vascular disorders, kidney failure, thromboembolicdisorders, fibrotic disorders and arteriosclerosis.

The present invention further provides the compounds according to theinvention for use in a method for the treatment and/or prophylaxis ofheart failure, angina pectoris, hypertension, pulmonary hypertension,ischaemias, vascular disorders, kidney failure, thromboembolicdisorders, fibrotic disorders and arteriosclerosis.

The present invention further provides for the use of the compoundsaccording to the invention for producing a medicament for treatmentand/or prophylaxis of disorders, in particular the disorders mentionedabove.

The present invention further provides for the use of the compoundsaccording to the invention for producing a medicament for treatmentand/or prophylaxis of heart failure, angina pectoris, hypertension,pulmonary hypertension, ischaemias, vascular disorders, kidney failure,thromboembolic disorders, fibrotic disorders and arteriosclerosis.

The present invention further provides a method for treatment and/orprophylaxis of disorders, in particular the disorders mentioned above,using an effective amount of at least one of the compounds according tothe invention.

The present invention further provides a method for treatment and/orprophylaxis of heart failure, angina pectoris, hypertension, pulmonaryhypertension, ischaemias, vascular disorders, kidney failure,thromboembolic disorders, fibrotic disorders and arteriosclerosis usingan effective amount of at least one of the compounds according to theinvention.

The compounds according to the invention can be employed alone or, ifrequired, in combination with other active compounds. The presentinvention further provides medicaments comprising at least one of thecompounds according to the invention and one or more further activecompounds, especially for the treatment and/or prophylaxis of theaforementioned disorders. Preferred examples of suitable active compoundcombinations include:

organic nitrates and NO donors, for example sodium nitroprusside,nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomineor SIN-1, and inhaled NO;

compounds which inhibit the breakdown of cyclic guanosine monophosphate(cGMP), such as, for example, inhibitors of phosphodiesterases (PDE) 1,2 and/or 5, in particular PDE 5 inhibitors such as sildenafil,vardenafil and tadalafil;

agents having an antithrombotic effect, for example and with preferencefrom the group of platelet aggregation inhibitors, of anticoagulants orof profibrinolytic substances;

active compounds which lower blood pressure, for example and preferablyfrom the group of calcium antagonists, angiotensin All antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, alpha-receptorblockers, beta-receptor blockers, mineralocorticoid receptorantagonists, and of diuretics; and/or

active compounds which alter lipid metabolism, for example and withpreference from the group of thyroid receptor agonists, cholesterolsynthesis inhibitors such as, by way of example and preferably, HMG-CoAreductase inhibitors or squalene synthesis inhibitors, of ACATinhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gammaand/or PPAR-delta agonists, cholesterol absorption inhibitors, lipaseinhibitors, polymeric bile acid adsorbents, bile acid reabsorptioninhibitors and lipoprotein(a) antagonists;

Agents having antithrombotic activity preferably mean compounds from thegroup of platelet aggregation inhibitors, of anticoagulants or ofprofibrinolytic substances.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a plateletaggregation inhibitor such as, by way of example and preferably,aspirin, clopidogrel, ticlopidin or dipyridamol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitorsuch as, by way of example and preferably, ximelagatran, dabigatran,melagatran, bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist such as, by way of example and preferably, tirofiban orabciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xa inhibitorsuch as, by way of example and preferably, rivaroxaban (BAY 59-7939),DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux,idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021,DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist such as, by way of example and preferably, coumarin.

Agents which lower blood pressure are preferably understood to meancompounds from the group of calcium antagonists, angiotensin Allantagonists, ACE inhibitors, endothelin antagonists, renin inhibitors,alpha-receptor blockers, beta-receptor blockers, mineralocorticoidreceptor antagonists, and the diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonistsuch as, by way of example and preferably, nifedipine, amlodipine,verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-1 receptorblocker such as, by way of example and preferably, prazosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta receptorblocker such as, by way of example and preferably, propranolol,atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol,bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol,metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol,labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol orbucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin Allantagonist such as, by way of example and preferably, losartan,candesartan, valsartan, telmisartan or embusartan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor suchas, by way of example and preferably, enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an endothelinantagonist such as, by way of example and preferably, bosentan,darusentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a renin inhibitorsuch as, for example and preferably, aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a mineralocorticoidreceptor antagonist such as, for example and preferably, spironolactoneor eplerenone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a loop diuretic suchas, for example, furosemide, torasemide, bumetanide and piretanide, withpotassium-sparing diuretics such as, for example, amiloride andtriamterene, with aldosterone antagonists such as, for example,spironolactone, potassium canrenoate and eplerenone and also thiazidediuretics such as, for example, hydrochlorothiazide, chlorthalidone,xipamide and indapamide.

Active compounds which alter lipid metabolism are preferably understoodto mean compounds from the group of CETP inhibitors, thyroid receptoragonists, cholesterol synthesis inhibitors such as HMG-CoA reductaseinhibitors or squalene synthesis inhibitors, of ACAT inhibitors, MTPinhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists,cholesterol absorption inhibitors, polymeric bile acid adsorbents, bileacid reabsorption inhibitors, lipase inhibitors and lipoprotein(a)antagonists;

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor suchas, by way of example and preferably, dalcetrapib, BAY 60-5521,anacetrapib or CETP vaccine (CETi-1).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid receptoragonist such as, by way of example and preferably, D-thyroxin,3,5,3′-triiodothyronin (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a HMG-CoA reductaseinhibitor from the class of the statins such as, by way of example andpreferably, lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor such as, by way of example and preferably, BMS-188494 orTAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitorsuch as, by way of example and preferably, avasimibe, melinamide,pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor suchas, by way of example and preferably, implitapide, BMS-201038, R-103757or JTT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-gamma agonistsuch as, by way of example and preferably, pioglitazone orrosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-delta agonistsuch as, for example and preferably, GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor such as, by way of example and preferably,ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitor, apreferred example being orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric bile acidadsorbent such as, by way of example and preferably, cholestyramine,colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a bile acidreabsorption inhibitor such as, by way of example and preferably, ASBT(=IBAT) inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741,SC-435 or SC-635

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an lipoprotein(a)antagonist such as, by way of example and preferably, gemcabene calcium(CI-1027) or nicotinic acid.

The present invention further provides medicaments which comprise atleast one compound according to the invention, typically together withone or more inert, nontoxic, pharmaceutically suitable auxiliaries, andthe use thereof for the aforementioned purposes.

The compounds according to the invention may act systemically and/orlocally. For this purpose, they can be administered in a suitablemanner, for example by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival,otic route, or as an implant or stent.

The compounds according to the invention can be administered inadministration forms suitable for these administration routes.

Suitable administration forms for oral administration are those whichwork according to the prior art, which release the compounds accordingto the invention rapidly and/or in a modified manner and which containthe compounds according to the invention in crystalline and/oramorphized and/or dissolved form, for example tablets (uncoated orcoated tablets, for example with gastric juice-resistant orretarded-dissolution or insoluble coatings which control the release ofthe compound according to the invention), tablets or films/wafers whichdisintegrate rapidly in the oral cavity, films/lyophilizates or capsules(for example hard or soft gelatin capsules), sugar-coated tablets,granules, pellets, powders, emulsions, suspensions, aerosols orsolutions.

Parenteral administration can bypass an absorption step (e.g.intravenously, intraarterially, intracardially, intraspinally orintralumbally) or include an absorption (e.g. intramuscularly,subcutaneously, intracutaneously, percutaneously or intraperitoneally).Administration forms suitable for parenteral administration includepreparations for injection and infusion in the form of solutions,suspensions, emulsions, lyophilizates or sterile powders.

For the other administration routes, suitable examples are inhalablemedicament forms (including powder inhalers, nebulizers), nasal drops,solutions or sprays, tablets, films/wafers or capsules for lingual,sublingual or buccal administration, suppositories, ear or eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakingmixtures), lipophilic suspensions, ointments, creams, transdermaltherapeutic systems (e.g. patches), milk, pastes, foams, sprinklingpowders, implants or stents.

Oral or parenteral administration is preferred, especially oraladministration.

The compounds according to the invention can be converted to theadministration forms mentioned. This can be done in a manner known perse, by mixing with inert, nontoxic, pharmaceutically suitableexcipients. These excipients include carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersing or wetting agents (forexample sodium dodecylsulphate, polyoxysorbitan oleate), binders (forexample polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants, for example ascorbicacid), dyes (e.g. inorganic pigments, for example iron oxides) andflavour and/or odour correctants.

In general, it has been found to be advantageous in the case ofparenteral administration to administer amounts of about 0.001 to 1mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieveeffective results. In the case of oral administration, the dosage isabout 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and mostpreferably 0.1 to 10 mg/kg of body weight.

It may nevertheless be necessary where appropriate to deviate from thestated amounts, specifically as a function of the body weight, route ofadministration, individual response to the active compound, nature ofthe preparation and time or interval over which administration takesplace. For instance, in some cases, less than the aforementioned minimumamount may be sufficient, while in other cases the upper limit mentionedmust be exceeded. In the case of administration of relatively largeamounts, it may be advisable to divide these into several individualdoses over the course of the day.

The working examples which follow illustrate the invention. Theinvention is not limited to the examples.

The percentages in the tests and examples which follow are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration data for liquid/liquidsolutions are based in each case on volume.

A. Examples

Abbreviations and acronyms:

aq. aqueous solution

calc. calculated

br s broad singlet (in NMR)

DCI direct chemical ionization (in MS)

dec. decomposition point

DMF dimethylformamide

DMSO dimethyl sulphoxide

DSC dynamic differential calorimetry

eq. equivalent(s)

ESI electrospray ionization (in MS)

Et ethyl

fnd. found

h hour(s)

HPLC high-pressure high-performance liquid chromatography

HRMS high-resolution mass spectrometry

conc. concentrated

LC-MS liquid chromatography-coupled mass spectrometry

LiHMDS lithium hexamethyldisilazide

Me methyl

min minute(s)

MS mass spectrometry

NMR nuclear magnetic resonance spectrometry

Pd₂dba₃ tris(dibenzylideneacetone)dipalladium

Ph phenyl

PLM polarized light microscope

RT room temperature

R_(t) retention time (in HPLC)

TGA thermogravimetric analysis

THF tetrahydrofuran

UV ultraviolet spectrometry

v/v volume to volume ratio (of a solution)

LC/MS Methods:

Method 1: MS instrument type: Waters ZQ; apparatus type HPLC: Agilent1100 Series; UV DAD; column: Thermo Hypersil GOLD 3μ 20 mm×4 mm; mobilephase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phaseB: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0min 100% A 3.0 min 10% A 4.0 min 10% A 4.1 min 100% A (flow rate 2.5ml/min); oven: 55° C.; flow rate: 2 ml/min; UV detection: 210 nm.

Method 2: Instrument: Waters ACQUITY SQD UPLC System; column: WatersAcquity UPLC HSS T3 1.8μ 50×1 mm; mobile phase A: 1 l of water+0.25 mlof 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 mlof 99% strength formic acid; gradient: 0.0 min 90% A→1.2 min 5% A→2.0min 5% A oven: 5° C.; flow rate: 0.40 ml/min; UV detection: 210 -400 nm.

Method 3: Instrument: Micromass Quattro Premier with Waters UPLCAcquity; column: Thermo Hypersil GOLD 1.9μ 50 mm×1 mm; mobile phase A: 1l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A0.1 min 90% A 1.5 min 10% A 2.2 min 10% A; oven 50° C.; flow rate: 0.33ml/min; UV detection: 210 nm.

General methods:

PLM: The polarized light microscopy was carried out using a Clemex PS3polarized light microscope particle size system with a Leica DMmicroscope procided with 50X, 100X, 200X, and 500X lenses, ahigh-resolution monochrome 1600×1200 pixel digital camera and amotorized X-Y Marzhauser station (controlled by a Clemex ST-2000controller). The samples of the crystalline material were measured on aglass slide (76×26 mm) in a drop of oil, the sample being covered with acover glass (22×40 mm)

DSC: The melting points were determined by dynamic differentialcalorimetry. The determination was carried out using a Mettler-Toledo823^(e) DSC instrument provided with a TSO801RO sample robot andSTAR^(e) software. About 1.5 to 3 mg of the sample were weighed out intoa small aluminium pan, which was then closed with a perforated cap. Theheat flow was measured in a temperature range of from 30 to 400° C. at aheating rate of 10° C./min and under an argon stream of 30 ml/min.

TGA: The thermogravimetric analysis was carried out using aMettler-Toledo TGA/SDTA851^(e) TGA instrument provided with a TSO801ROsample robot and STARe software. About 1.5 to 3 mg of the sample wereweighed out into a small open aluminium pan (100 μl). The sample weightwas measured in a temperature range of from 30 to 400° C. at a heatingrate of 10° C./min and under an argon stream of 30 ml/min.

The elemental analyses were carried out by Currenta GmbH & Co. usingmethods known to the person skilled in the art, in accordance withindustry norm DIN-ISO 17025.

Starting Materials and Intermediates:

Example 1A

2,6-Dichloro-5-fluoronicotinamide

A suspension of 25 g (130.90 mmol) of2,6-dichloro-5-fluoro-3-cyanopyridine in conc. sulphuric acid (125 ml)was stirred at 60-65° C. for 1 h. After cooling to RT, the contents ofthe flask were poured into ice-water and extracted three times withethyl acetate (100 ml each time). The combined organic phases werewashed with water (100 ml) and then with saturated aqueous sodiumhydrogen carbonate solution (100 ml), dried and concentrated on a rotaryevaporator. The material obtained was dried under high vacuum.

Yield: 24.5 g (90% of theory)

¹H NMR (400 MHz, DMSO-d₆): δ=7.95 (br s, 1H), 8.11 (br s, 1H), 8.24 (d,1H).

Example 2A

2-Chloro-5-fluoronicotinamide

At RT, 44 g (210.58 mmol) of 2,6-dichloro-5-fluoronicotinamide wereadded to a suspension of 21.9 g (335.35 mmol) of zinc in methanol (207ml). Acetic acid (18.5 ml) was then added, and the mixture was heatedwith stirring at reflux for 24 h. The contents of the flask were thendecanted from the zinc, and ethyl acetate (414 ml) and saturated aqueoussodium hydrogen carbonate solution (414 ml) were added, followed byintense extractive stirring. Subsequently the reaction mixture wasfiltered with suction through kieselguhr and the filter product waswashed three times with ethyl acetate (517 ml each time). The organicphase was separated off and the aqueous phase was washed with ethylacetate (258 ml). The combined organic phases were washed once withsaturated aqueous sodium hydrogen carbonate solution (414 ml), dried andconcentrated under reduced pressure. Dichloromethane (388 ml) was addedto the crystals obtained in this manner, and the mixture was stirred for20 min. The mixture was once more filtered off with suction, washed withdiethyl ether and sucked dry.

Yield: 20.2 g (53% of theory)

¹H NMR (400 MHz, DMSO-d₆): δ=7.87 (br s, 1H), 7.99 (dd, 1H), 8.10 (br s,1H), 8.52 (d, 1H).

Example 3A

2-Chloro-5-fluoronicotinonitrile

81.2 ml (582.25 mmol) of triethylamine were added to a suspension of46.2 g (264.66 mmol) of 2-chloro-5-fluoronicotinamide in dichloromethane(783 ml), and the mixture was cooled to 0° C. Then, with stirring, 41.12ml (291.13 mmol) of trifluoroacetic anhydride were added slowly dropwiseand the mixture was stirred at 0° C. for 1.5 h. The reaction solutionwas subsequently washed twice with saturated aqueous sodium bicarbonatesolution (391 ml each time), dried and concentrated under reducedpressure.

Yield: 42.1 g (90% of theory)

¹H NMR (400 MHz, DMSO-d₆): δ=8.66 (dd, 1H), 8.82 (d, 1H).

Example 4A

5-Fluoro-1H-pyrazolo[3,4-b]pyridine-3-amine

A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrilewas initially charged in 1,2-ethanediol (380 ml), and hydrazine hydrate(119.6 ml, 2.459 mol) was then added. The mixture was heated underreflux with stirring for 4 h. The product precipitated on cooling. Water(380 ml) was added to the yellow crystals, and the mixture was subjectedto extractive stirring at RT for 10 min. The suspension was thenfiltered with suction over a frit, and the filter product was washedwith water (200 ml) and with −10° C. cold THF (200 ml). The residue wasdried under high vacuum over phosphorus pentoxide.

Yield: 22.8 g (61% of theory)

¹H NMR (400 MHz, DMSO-d₆): δ=5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H),12.07 (m, 1H).

Example 5A

5-Fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine

10 g (65.75 mmol) of 5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-amine wereinitially charged in THF (329 ml), and the mixture was cooled to 0° C.16.65 ml (131.46 mmol) of boron trifluoride diethyl ether complex werethen added slowly. The reaction mixture was cooled further to −10° C. Asolution of 10.01 g (85.45 mmol) of isopentyl nitrite in THF (24.39 ml)was then added slowly, and the mixture was stirred for a further 30 min.The mixture was diluted with cold diethyl ether (329 ml) and theresulting solid was isolated by filtration. A little at a time, thediazonium salt thus prepared was added to a cold (0° C.) solution of12.81 g (85.45 mmol) of sodium iodide in acetone (329 ml), and themixture was stirred at RT for 30 min. The reaction mixture was pouredinto ice-water (1.8 1) and extracted twice with ethyl acetate (487 mleach time). The collected organic phases were washed with saturatedaqueous sodium chloride solution (244 ml), dried, filtered andconcentrated. This gave 12.1 g (86% purity, 60% of theory) of thedesired compound in the form of a brown solid. The crude product wasreacted without further purification.

LC-MS (method 1): R₁=1.68 min; MS (ESIpos): m/z=264 (M+H)⁺.

Example 6A

5-Fluoro-1-(2-fluorobenzyl)-3 -iodo- 1H-pyrazolo[3,4-b]pyridine

141 g (462.11 mmol) of the compound from Example 5A were introduced intoDMF (2538 ml), and 96.09 g (508.32 mmol) of 2-fluorobenzyl bromide and165.62 g (508.32 mmol) of caesium carbonate were then added. The mixturewas stirred at RT for two hours. The reaction mixture was then pouredinto saturated aqueous sodium chloride solution (13 670 ml) andextracted twice with ethyl acetate (5858 ml). The collected organicphases were washed with saturated aqueous sodium chloride solution (3905ml), dried, filtered and concentrated. The residue was chromatographedon silica gel (mobile phase: petroleum ether/ethyl acetate 97:3) and theproduct fractions were concentrated. The resulting solid was dissolvedin dichloromethane and washed once with saturated aqueous sodiumthiosulphate solution (500 ml) and then with saturated aqueous sodiumchloride solution (500 ml). The product was concentrated to dryness andthe residue was suspended in diethyl ether, isolated by filtration withsuction and dried under high vacuum. This gave 106.6 g (62% of theory)of the desired compound.

¹H NMR (400 MHz, DMSO-d₆): δ=5.73 (s, 2H), 7.13-7.26 (m, 3H), 7.33-7.41(m, 1H), 7.94 (dd, 1H), 8.69-8.73 (m, 1H).

Example 7A

2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-nitropyrimidine-4,6-diamine

Under argon, 860 mg (2.32 mmol) of the compound from Example 6A wereintroduced into 1,4-dioxane (86 ml), and the reaction mixture wasflushed with argon for 10 min. Then 3.51 ml (6.95 mmol) ofhexabutylditin and 483 mg (2.55 mmol) of2-chloro-5-nitropyrimidine-4,6-diamine (prepared by the method ofHelvetica Chimica Acta (1951), 34, 835-40) were added. Subsequently 860mg (0.744 mmol) of tetrakis(triphenylphosphine)palladium(0) were addedand the reaction mixture was heated at reflux overnight. The mixture wasthen cooled to RT, water was added and the mixture was extracted twicewith ethyl acetate. The collected organic phases were dried over sodiumsulphate, filtered and concentrated. The residue was subjected toextractive stirring in ethyl acetate, and the solid was isolated byfiltration and dried under high vacuum. This gave 355 mg (62% purity,24% of theory) of the desired compound. The crude product was reactedwithout further purification.

LC-MS (method 2): R_(t)=1.03 min

MS (ESIpos): m/z=399 (M+H)⁺

Example 8A

5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

A suspension of 16.03 g (43.19 mmol) of5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine (Example6A) and 4.25 g (47.51 mmol) of copper cyanide was initially charged inDMSO (120 ml) and stirred at 150° C. for 2 h. After cooling, thecontents of the flask were cooled to about 40° C. and poured into asolution of conc. aqueous ammonia (90 ml) and water (500 ml), ethylacetate (200 ml) was added and the mixture was subjected to briefextractive stirring. The aqueous phase was separated off and extractedtwo more times with ethyl acetate (200 ml each time). The combinedorganic phases were washed twice with 10% strength aqueous sodiumchloride solution (100 ml each time), dried and concentrated underreduced pressure. The crude product was reacted without furtherpurification.

Yield: 11.1 g (91% of theory)

¹H NMR (400 MHz, DMSO-d₆): δ=5.87 (s, 2H), 7.17-7.42 (m, 4H), 8.52 (dd,1H), 8.87 (dd, 1H).

Example 9A

5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamideacetate

11.1 g (41.07 mmol) of 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (Example8A) were added to 2.22 g (41.07 mmol) of sodium methoxide in methanol(270 ml), and the mixture was stirred at RT for 2 h. 2.64 g (49.29 mmol)of ammonium chloride and acetic acid (9.17 ml) were then added, and themixture was heated at reflux overnight. The mixture was thenconcentrated to dryness and the residue was taken up in water (100 ml)and ethyl acetate (100 ml) and adjusted to a pH of 10 using 2N aqueoussodium hydroxide solution. The mixture was stirred intensively at RT forabout 1 h. The resulting suspension was filtered with suction and thefilter product was washed with ethyl acetate (100 ml), with water (100ml) and once more with ethyl acetate (100 ml). The residue was driedunder high vacuum over phosphorus pentoxide.

Yield: 9.6 g (78% of theory)

MS (ESIpos): m/z=288 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=1.85 (s, 3H), 5.80 (s, 2H), 7.14-7.25 (m,3H), 7.36 (m, 1H), 8.42 (dd, 1H), 8.72 (dd, 1H).

Example 10A

2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazenyl]pyrimidine-4,6-diamine

With stirring, 3.85 g (41.34 mmol) of aniline were added to water (40ml) and conc. hydrochloric acid (7.07 ml), and this mixture was cooledto 0° C. A solution of 2.85 g (41.34 mmol) of sodium nitrite in water(21 ml) was then added dropwise at between 0° C. and 5° C., followed bystirring at 0° C. for 15 min. Thereafter, at 0° C., a solution of 4.28 g(52.25 mmol) of sodium acetate in water (19 ml) was added rapidlydropwise, and then, with thorough stirring, a solution of 2.73 g (41.34mmol) of malononitrile in ethanol (10 ml) was added dropwise. After 2 hat 0° C., the resulting precipitate was isolated by filtration withsuction and washed three times with water (50 ml each time) and withpetroleum ether (50 ml). The residue, still moist, was dissolved in DMF(46 ml) and added dropwise at precisely 85° C. to a solution of 9.5 g(33.07 mmol) of 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide acetate (Example 9A) in DMF (46 ml) andtriethylamine (5.76 ml). The mixture was then stirred at 100° C. for 4 hand left to cool to RT overnight. The mixture was poured into water (480ml) and subjected to extractive stirring at RT for 1 h. After theprecipitate had been isolated by filtration with suction, it was washedtwice with water (100 ml each time) and twice with methanol (50 ml eachtime) and then dried under a high vacuum.

Yield: 9.6 g (59% of theory)

LC-MS (method 2): R_(t)=1.21 min

MS (ESIpos): m/z=458 (M+H)⁺

Example 11A

2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine

Variant A: Preparation starting from Example 7A:

In pyridine (30 ml), 378 mg (0.949 mmol) of the compound from Example 7Awere introduced and then 143 mg (0.135 mmol) of palladium (10% oncarbon) were added. The mixture was hydrogenated overnight at RT understandard hydrogen pressure. The suspension was then filtered throughkieselguhr and the filtercake was washed with ethanol. The filtrate wasconcentrated and yielded 233 mg (81% purity, 51% of theory) of thedesired compound, which was reacted without further purification.

Variant B: Preparation starting from Example 10A:

In DMF (800 ml), 39.23 g (85.75 mmol) of the compound from Example 10Awere introduced and then 4 g of palladium (10% on carbon) were added.The mixture was hydrogenated with stirring overnight under standardhydrogen pressure. The batch was filtered over kieselguhr and the filterproduct was washed with a little DMF and then with a little methanol,and concentrated to dryness. The residue was admixed with ethyl acetateand stirred vigorously, and the precipitate was filtered off withsuction, washed with ethyl acetate and diisopropyl ether and dried undera high vacuum over Sicapent.

Yield: 31.7 g (100% of theory) LC-MS (method 2): R_(t) =0.78 min MS(ESIpos): m/z=369 (M+H)⁺

Working Examples: Example 1:

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

In pyridine (600 ml), 31.75 g (86.20 mmol) of the compound from Example11A were introduced under argon and cooled to 0° C. Then a solution of6.66 ml (86.20 mmol) of methyl chloroformate in dichloromethane (10 ml)was added dropwise and the mixture was stirred at 0° C. for 1 h.Thereafter the reaction mixture was brought to RT, concentrated underreduced pressure and co-distilled repeatedly with toluene. The residuewas stirred with water/ethanol and then filtered off on a frit, afterwhich it was washed with ethanol and ethyl acetate. Subsequently theresidue was again stirred with diethyl ether, isolated by filtrationwith suction and then dried under a high vacuum.

Yield: 24.24 g (65% of theory)

LC-MS (method 2): R_(t)=0.79 min

MS (ESIpos): m/z=427 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.62 (br. s, 3H), 5.79 (s, 2H), 6.22 (br.s, 4H), 7.10-7.19 (m, 2H), 7.19-7.26 (m, 1H), 7.32-7.40 (m, 1H), 7.67and 7.99 (2 br. s, 1H), 8.66 (m, 1H), 8.89 (dd, 1H).

Example 2:

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate

A quantity of 200 mg (0.469 mmol) of methyl4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-ylcarbamate (Example 1) was introduced inTHF (5 ml) at 0° C. Then 0.704 ml (0.704 mmol) of lithiumhexamethyldisilazane solution (1M in THF) was added and the mixture wasstirred at this temperature for 20 min. Subsequently 43.8 μl (0.704mmol) of iodomethane were added and the mixture was warmed to RT. After1 h at this temperature, reaction was terminated with water (1 ml) andthe reaction mixture was concentrated, the residue being separated bymeans of preparative RP-HPLC (water (+0.05% formic acid)-acetonitrilegradient).

Yield: 90 mg (44% of theory)

LC-MS (method 2): R_(t)=0.85 min

MS (ESIpos): m/z=441 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.00 (s, 3H), 3.53 and 3.66 (2s, 3H), 5.81(s, 2H), 6.57 (br. s, 4H), 7.13 (m, 2H), 7.22 (m, 1H), 7.35 (m, 1H),8.67 (m, 1H), 8.87 (dd, 1H).

Example 3:

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}(2,2,2-trifluoroethyl)carbamate

A quantity of 3.470 g (8.138 mmol) of the compound from Example 1 wassuspended in 35 ml of THF, admixed at 0° C. with 358 mg (8.952 mmol) ofsodium hydride (60% suspension in mineral oil) and stirred at 0° C. for90 min, in the course of which a solution was formed. A quantity of2.519 g (8.952 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonatewas added and the mixture was stirred at RT for 48 h. It was thenstirred with water and concentrated on a rotary evaporator. The residuewas taken up in ethyl acetate, and the organic phase was washed twicewith water and dried over sodium sulphate. This gave 5.005 g of thetarget compound (79% of theory, purity by HPLC 65%). A quantity of 250mg of the residue was purified by means of preparative HPLC (mobilephase: methanol/water, gradient 30:70 90:10).

LC-MS (method 2): R_(t)=0.97 min; MS (Elpos): m/z=509 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.63 (s, 3H), 4.06-4.15 (m, 2H), 5.80(s, 2H), 6.46 (br s, 4H) 7.11-7.15 (m, 2H), 7.20-7.25 (m, 1H), 7.33-7.38(m, 1H), 8.66 (dd, 1H), 8.91 (dd, 1H).

Example 4

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatehydrochloride

A solution of 100 mg (0.235 mmol) of Example 1 in 2 ml of 1,4-dioxanewas prepared in a brown 5 ml glass bottle. In succession, 2 ml ofisopropanol and 235 μl (0.235 mmol) of 1M hydrochloric acid were addedto this solution, and the solution was stirred at RT until the solventshad evaporated. Air-drying gave 102 mg (94% of theory) of the titlecompound.

PLM (100×): crystalline

DSC: 224° C. (dec., ΔH=189 J/g)

TGA: 1% weight loss at 80° C.

LC-MS (method 3): R_(t)=0.91 min

MS (ESIpos): m/z=427 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.35 and 3.65 (2 s, 3H), 5.92 (s,2H), 7.15 (dd, 1H), 7.25 (m, 2H), 7.37 (m, 1H), 7.75 (br s, 4H), 8.08and 8.39 (2 s, 1H), 8.82 (m, 2H), 13.2 (br s, 1H).

Elemental analysis for C₁₉H₁₆F₂N₈O₂+HCl:

calculated: % C 49.31; % H 3.70; % N 24.21;

measured: % C 49.5; % H 3.7; % N 24.3.

Example 5

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatesulphate

A solution of 100 mg (0.235 mmol) of Example 1 in 2 ml of 1,4-dioxanewas prepared in a brown 5 ml glass bottle. In succession, 2 ml ofisopropanol and a solution of 938 μ1 (0.235 mmol) of 0.25M sulphuricacid were added to this solution, and the solution was stirred at RTuntil the solvents had evaporated. Air-drying gave 103 mg (83.7% oftheory) of the title compound.

PLM (100×): crystalline

DSC: 242° C. (dec., ΔH=115 J/g)

TGA: no weight loss prior to decomposition

LC-MS (method 3): R_(t)=0.91 min

MS (ESIpos): m/z=427 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.56 and 3.66 (2 s, 3H), 5.93 (s,2H), 7.16 (m, 2H), 7.25 (dd, 1H), 7.38 (m, 1H), 7.59 (br s, 4H), 8.03and 8.32 (2 s, 1H), 8.82 (m, 2H), 13.0 (br s, 1H).

Elemental analysis for C₁₉H₁₆F₂N₈O₂+H₂SO₄:

calculated: % C 43.51; % H 3.46; % N 21.37;

measured: % C 43.6; % H 3.4; % N 21.2.

Example 6

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatephosphate

A solution of 100 mg (0.235 mmol) of Example 1 in 2 ml of 1,4-dioxanewas prepared in a brown 5 ml glass bottle. In succession, 2 ml of THFand a solution of 16 μl (0.235 mmol) of 85% strength phosphoric acid in0.3 ml of water were added to this solution, and the solution wasstirred at RT until the solvents had evaporated. Air-drying gave 105 mg(85.4% of theory) of the title compound.

PLM (100×): crystalline

DSC: 183° C. (dec., ΔH=65 J/g)

TGA: 6% weight loss prior to decomposition

LC-MS (method 3): R_(t)=0.91 min

MS (ESIpos): m/z=427 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.57 and 3.62 (2 s, methyl signalobscured by water signal, 3H), 5.79 (s, 2H), 6.22 (br s, 4H), 7.15 (m,2H), 7.22 (dd, 1H), 7.36 (m, 1H), 7.67 and 7.99 (2 s, 1H), 8.66 (m, 1H),8.90 (m, 1H).

³¹P-NMR (400 MHz, DMSO-d₆): δ [ppm]=−1.1

Elemental analysis for C₁₉H₁₆F₂N₈O₂+H₃PO₄+2 H₂O:

calculated: % C 40.72; % H 4.14; % N 19.99;

measured: % C 40.5; % H 4.0; % N 19.5.

Example 7

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatemesylate

A solution of 100 mg (0.235 mmol) of Example 1 in 2 ml of 1,4-dioxanewas prepared in a brown 5 ml glass bottle. In succession, 2 ml ofethanol and a solution of 22.5 mg (0.235 mmol) of methanesulphonic acidin 0.3 ml of water were added to this solution, and the solution wasstirred at RT until the solvents had evaporated. Air-drying gave 103 mg(84% of theory) of the title compound.

PLM (100×): crystalline

DSC: 154° C. (ΔH=11.7 J/g), 167° C. (ΔH=−5 J/g), 215.2° C. (dec, ΔH=56.1J/g)

TGA: gradual weight loss during the measurement

LC-MS (method 3): R_(t)=0.91 min

MS (ESIpos): m/z=427 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.31 (s, 3H), 3.57 and 3.66 (2 s,3H), 5.93 (s, 2H), 7.17 (m, 2H), 7.25 (dd, 1H), 7.39 (m, 1H), 7.66 (sbr, 4H), 8.06 and 8.34 (2 s, 1H), 8.81 (dd, 1H), 8.83 (s, 1H), 13.0 (brs, 1H).

Elemental analysis for C₁₉H₁₆F₂N₈O₂+CH₄O₃S+H₂O:

calculated: % C 44.44; % H 4.14; % N 20.7;

measured: % C 44.3; % H 4.1; % N 20.2.

Example 8

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateethane-1,2-disulphonate

A solution of 100 mg (0.235 mmol) of Example 1 in 2 ml of 1,4-dioxanewas prepared in a brown 5 ml glass bottle. In succession, 2 ml ofisopropanol and 44.6 mg (0.235 mmol) of ethane-1,2-disulphonic acid wereadded to this solution, and the solution was stirred at RT until thesolvents had evaporated. Air-drying gave 111 mg (73.7% of theory) of thetitle compound.

PLM (100×): predominantly crystalline

DSC: 97° C. (dec., ΔH=103 J/g)

TGA: gradual weight loss during the measurement

LC-MS (method 3): R_(t)=0.90 min

MS (ESIpos): m/z=427 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.66 (s, 4H), 3.57 and 3.66 (2 s,methyl signal obscured by water signal, 3H), 5.93 (s, 2H), 7.17 (m, 2H),7.25 (m, 1H), 7.39 (m, 1H), 8.05 and 8.35 (2 s, 1H), 8.80 (dd, 1H), 8.84(s, 1H).

Elemental analysis for C₁₉H₁₆F₂N₈O₂+C₂H₆O₆S₂+0.25 H₂O₂O+0.25 C₄H₈O₂:

calculated: % C 41.09; % H 3.84; % N 17.42;

measured: % C 41.2; % H 4.2; % N 17.6.

Example 9

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatemaleate

A solution of 100 mg (0.235 mmol) of Example 1 in 2 ml of 1,4-dioxanewas prepared in a brown 5 ml glass bottle. In succession, 2 ml ofisopropanol and 27.2 mg (0.235 mmol) of maleic acid were added to thissolution, and the solution was stirred at RT until the solvents hadevaporated. Air-drying gave 108 mg (84.9% of theory) of the titlecompound.

PLM (100×): crystalline

DSC: 192° C. (dec., ΔH=173 J/g)

TGA: 3% weight loss prior to decomposition

LC-MS (method 3): R_(t)=0.91 min

MS (ESIpos): m/z=427 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.56 and 3.64 (2 s, obscured bydioxane signal, 3H), 5.85 (s, 2H), 6.16 (s, 2H), 6.9 (br s, 4H), 7.15(m, 2H), 7.23 (dd, 1H), 7.37 (m, 1H), 7.85 and 8.13 (2 s, 1H), 8.73 (s,1H), 8.86 (dd, 1H).

Elemental analysis for C₁₉H₁₆F₂N₈O₂+C₄H₄O₄+0.5 H₂O₂O+0.5 C₄H₈O₂:

calculated: % C 50.42; % H 4.23; % N 18.82;

measured: % C 50.7; % H 3.9 ; % N 18.8.

Example 10

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatenitrate

A solution of 100 mg (0.235 mmol) of Example 1 in 2 ml of isopropanolwas prepared in a brown 5 ml glass bottle. In succession, 2 ml ofisopropanol and 0.235 μ1 (0.235 mmol) of 1M nitric acid were added tothis solution, and the solution was stirred at RT until the solvents hadevaporated. Air-drying gave 103 mg (89.7% of theory) of the titlecompound.

PLM (100×): crystalline

DSC: 175° C. (dec., ΔH=−224 J/g)

TGA: 3% weight loss prior to decomposition

LC-MS (method 3): R_(t)=0.91 min

MS (ESIpos): m/z=427 (M+H)⁺

¹NMR (400 MHz, DMSO-d₆): δ [ppm]=3.57 and 3.66 (2 s, 3H), 5.93 (s, 2H),7.16 (m, 2H), 7.25 (dd, 1H), 7.38 (m, 1H), 7.65 (br s, 4H), 8.02 and8.32 (2 s, 1H), 8.80 (dd, 1H), 8.83 (s, 1H), 13.0 (br s, 1H).

Elemental analysis for C₁₉H₁₆P₂N₈O₂+HNO₃+0.75 H₂O:

calculated: % C 45.38; % H 3.71; % N 25.07;

measured: % C 45.4; % H 3.7; % N 25.0.

B. Assessment of Pharmacological Activity

The pharmacological effect of the compounds according to the inventioncan be shown in the following assays:

B-1. Vasorelaxant effect in vitro

Rabbits are stunned by a blow to the neck and exsanguinated. The aortais removed, freed from adhering tissue and divided into rings of a widthof 1.5 mm. The rings are placed individually under an initial tension in5 ml organ baths with Krebs-Henseleit solution which is at 37° C., isgassed with carbogen and has the following composition (in each casemM): sodium chloride 119; potassium chloride: 4.8; calcium chloridedihydrate: 1; magnesium sulphate heptahydrate: 1.4; potassiumdihydrogenphosphate: 1.2; sodium bicarbonate: 25; glucose: 10. The forceof contraction is detected with Statham UC2 cells, amplified anddigitized via A/D converters (DAS-1802 HC, Keithley Instruments, Munich)and recorded in parallel on chart recorders. To produce a contraction,phenylephrine is added to the bath cumulatively in increasingconcentration. After several control cycles, the substance to beinvestigated is added in each further run in increasing dosage in eachcase, and the height of the contraction achieved is compared with theheight of the contraction reached in the last preceding run. Theconcentration necessary to reduce the height of the control value by 50%is calculated from this (IC₅₀ value). The standard administration volumeis 5 μl and the proportion of DMSO in the bath solution corresponds to0.1%.

Representative IC₅₀ values for the compounds according to the inventionare shown in the table below (Table 1):

TABLE 1 Example No. IC₅₀ [nM] 1 958 2 251 3 515

B-2. Effect on a Recombinant Guanylate Cyclase Reporter Cell Line

The cellular activity of the compounds according to the invention isdetermined using a recombinant guanylate cyclase reporter cell line, asdescribed in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

Representative values (MEC=minimum effective concentration) for thecompounds according to the invention are shown in the table below (Table2):

TABLE 2 Example No. MEC [μM] 1 0.3 2 0.1 3 0.03

B-3. Radiotelemetric Measurement of Blood Pressure on ConsciousSpontaneously Hypertensive Rats

A commercially available telemetry system from DATA SCIENCESINTERNATIONAL DSI, USA, is employed for the blood pressure measurementson conscious rats described below.

The system consists of 3 main components:

implantable transmitters (Physiotel® telemetry transmitter)

receivers (Physiotel® receiver) which are linked via a multiplexer (DSIData Exchange Matrix) to a

data acquisition computer.

The telemetry system makes it possible to continuously record bloodpressure, heart rate and body motions of conscious animals in theirusual habitat.

Animal Material

The investigations are carried out on adult female spontaneouslyhypertensive rats (SHR Okamoto) with a body weight of >200 g. SHR/NCrlfrom the Okamoto Kyoto School of Medicine, 1963 were a cross of maleWistar Kyoto rats with highly elevated blood pressure and female ratshaving a slightly elevated blood pressure and at F13 handed over to theU.S. National Institutes of Health.

After transmitter implantation, the experimental animals are housedsingly in type 3 Makrolon cages. They have free access to standard feedand water.

The day/night rhythm in the experimental laboratory is changed by theroom lighting at 6.00 am and at 7.00 pm.

Transmitter Implantation

The telemetry transmitters TA11 PA-C40 used are surgically implantedunder aseptic conditions in the experimental animals at least 14 daysbefore the first experimental use. The animals instrumented in this waycan be employed repeatedly after the wound has healed and the implanthas settled.

For the implantation, the fasted animals are anaesthetized withpentobarbital (Nembutal, Sanofi: 50 mg/kg i.p.) and shaved anddisinfected over a large area of their abdomens. After the abdominalcavity has been opened along the linea alba, the liquid-filled measuringcatheter of the system is inserted into the descending aorta in thecranial direction above the bifurcation and fixed with tissue glue(VetBonD™, 3M). The transmitter housing is fixed intraperitoneally tothe abdominal wall muscle, and layered closure of the wound isperformed.

An antibiotic (Tardomyocel COMP, Bayer, 1 ml/kg s.c.) is administeredpostoperatively for prophylaxis of infection.

Substances and Solutions

Unless indicated otherwise, the substances to be investigated areadministered orally by gavage in each case to a group of animals (n=6).The test substances are dissolved in suitable solvent mixtures, orsuspended in 0.5% strength Tylose, appropriate for an administrationvolume of 5 ml/kg of body weight.

A solvent-treated group of animals is employed as control.

Test Procedure

The telemetry measuring unit present is configured for 24 animals. Eachexperiment is recorded under an experiment number (Vyear month day).

Each of the instrumented rats living in the system is assigned aseparate receiving antenna (1010 Receiver, DSI).

The implanted transmitters can be activated externally by means of anincorporated magnetic switch and are switched to transmission in therun-up to the experiment. The emitted signals can be detected online bya data acquisition system (Dataquest™ A.R.T. for Windows, DSI) and beappropriately processed. The data are stored in each case in a filecreated for this purpose and bearing the experiment number.

In the standard procedure, the following are measured for 10-secondperiods in each case:

systolic blood pressure (SBP)

diastolic blood pressure (DBP)

mean arterial pressure (MAP)

heart rate (HR)

activity (ACT).

The acquisition of measured values is repeated under computer control at5-minute intervals. The source data obtained as absolute value arecorrected in the diagram with the currently measured barometric pressure(Ambient Pressure Reference Monitor; APR-1) and stored as individualdata. Further technical details are given in the extensive documentationfrom the manufacturing company (DSI).

Unless indicated otherwise, the test substances are administered at 9.00am on the day of the experiment. Following the administration, theparameters described above are measured over 24 hours.

Evaluation

After the end of the experiment, the acquired individual data are sortedusing the analysis software (DataquestTM A.R.T.™ Analysis). The blankvalue is assumed to be the time 2 hours before administration of thesubstance, so that the selected data set includes the period from 7.00am on the day of the experiment to 9.00 am on the following day.

The data are smoothed over a presettable time by determination of theaverage (15-minute average) and transferred as a text file to a storagemedium. The measured values presorted and compressed in this way aretransferred into Excel templates and tabulated. For each day of theexperiment, the data obtained are stored in a dedicated file carryingthe number of the experiment. Results and test protocols are filed inpaper form sorted by numbers.

Representative values for the compounds according to the invention areshown in the table below (Table 3):

TABLE 3 Example 1: Example 2: Dosage Dosage Dosage 0.3 mg/kg 3.0 mg/kg0.3 mg/kg Vehicle p.o. p.o. Vehicle p.o. hours after mean blood meanblood mean blood hours after mean blood mean blood substance pressurepressure pressure substance pressure pressure administration (mm Hg) (mmHg) (mm Hg) administration (mm Hg) (mm Hg) 0 153.6 151.0 149.0 0 149.0161.3 1 164.5 148.4 129.3 1 158.2 145.7 2 146.7 136.4 111.1 2 142.2130.5 3 145.4 130.6 106.0 3 149.2 121.5 4 149.6 129.1 107.8 4 152.3123.1 5 149.9 132.8 109.3 5 155.8 121.6 6 151.6 125.6 106.8 6 147.3123.8 7 147.6 131.9 110.9 7 147.3 124.4 8 147.5 131.8 109.8 8 149.3128.7 9 150.8 138.5 114.3 9 151.0 133.7 10 149.8 138.3 114.5 10 152.5139.2 11 154.0 138.9 115.6 11 150.3 137.9 12 145.3 137.7 118.8 12 146.2143.0 13 141.1 142.9 120.4 13 143.2 146.0 14 147.8 144.5 122.8 14 146.4149.2 15 151.0 143.8 125.8 15 150.5 152.3 16 151.3 146.3 131.5 16 145.3155.5 17 148.8 141.8 124.7 17 143.9 156.3 18 149.2 138.4 129.6 18 150.3157.3 19 151.2 149.2 135.6 19 147.7 156.9 20 152.6 145.1 135.2 20 153.4156.3 21 146.3 142.1 129.3 21 148.6 149.3 22 146.3 141.8 128.3 22 153.3147.1 23 150.3 143.6 130.2 23 151.1 153.1 24 147.4 135.1 130.8 24 154.1152.3

REFERENCES

Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Müssig, Georg Ertl andBjörn Lemmer: Experimental heart failure in rats: effects oncardiovascular circadian rhythms and on myocardial β-adrenergicsignaling. Cardiovasc Res 47 (2): 203-405, 2000; Kozo Okamoto:Spontaneous hypertension in rats. Int Rev Exp Pathol 7: 227-270, 1969;Maarten van den Buuse: Circadian Rhythms of Blood Pressure, Heart Rate,and Locomotor Activity in Spontaneously Hypertensive Rats as MeasuredWith Radio-Telemetry. Physiology & Behavior 55(4): 783-787, 1994

B-4. Determination of Pharmacokinetic Parameters Following Intravenousand Peroral Administration:

The pharmacokinetic parameters of the substance are determined in maleCD-1 mice, male Wistar rats and female beagles. The administrationvolume is 10 ml/kg for mice, 5 ml/kg for rats and 0.5 ml/kg for dogs.Intravenous administration is via a formulation of species-specificplasma/DMSO (99/1) in the case of mice and rats and viawater/PEG400/ethanol (50/40/10) in the case of dogs. For easier removalof blood, a silicone catheter is inserted into the right Vena jugularisexterna of the rats before the administration of substance. The surgicalintervention takes place one day prior to the experiment with isoflurananaesthesia and administration of an analgetic (atropine/rimadyl (3/1)0.1 ml s.c.). Substance administration is as i.v. bolus in the case ofmice, as i.v. bolus or via a 15-minute infusion in the case of rats andvia a 15-minute infusion in the case of dogs. Removal of blood is after0.033, 0.083, 0.17, 0.5, 1, 2, 3, 4, 6, 7 and 24 hours in the case ofmice and, after a 15-minute infusion, after 0.083, 0.25, 0.28 0.33,0.42, 0.75, 1, 2, 3, 4, 6, 7 and 24 hours in the case of dogs and ratsand after an i.v. bolus administration, after 0.033, 0.083, 0.17, 0.5,1, 2, 3, 4, 6, 7 and 24 hours in the case of rats. For all species, oraladministration of the dissolved substance via gavage is carried outbased on a water/PEG400/ethanol formulation (50/40/10). Here, theremoval of blood from rats and dogs is after 0.083, 0.17, 0.5, 0.75, 1,2, 3, 4, 6, 7 and 24 hours. The blood is removed into heparinized tubes.The blood plasma is then obtained by centrifugation; if required, it canbe stored at −20° C. until further processing.

An internal standard (ZK 228859) is added to the unknown samples,calibration samples and QCs, and the protein is precipitated usingexcess acetonitrile. After addition of an ammonium acetate buffer (0.01M, pH 6.8 (Example 1/3) or pH 3.0 (Example 2)) and subsequent vortexing,the mixture is centrifuged at 1000 g and the supernatant is examined byLC-MS/MS (API 4000, AB

Sciex). Chromatographic separation is carried out on an Agilent1100-HPLC. The injection volume is 10 μl. The separation column used isa Phenomenex Luna 5μ C8(2) 100A 50×2 mm, adjusted to a temperature of40° C. For Example 1, a binary mobile phase gradient at 400 μl/min isused (A: 0.01M ammonium acetate buffer pH 6.8, B: 0.1% formic acid inacetonitrile): 0 min (90% A), 1 min (90% A), 3.5 min (15% A), 4.5 min(15% A), 4.6 min (90% A), 7 min (90% A). For Example 2, a binary mobilephase gradient at 500 μl/min is used instead (A: 0.01M ammonium acetatebuffer pH 3.0, B: 0.1% formic acid in acetonitrile): 0 min (90% A), 1.5min (90% A), 3.5 min (10% A), 4.5 min (10% A), 5 min (90% A), 7 min (90%A). For Example 3, a binary mobile solvent gradient at 500 μl/min isused instead (A: 0.01M ammonium acetate buffer pH 6.8, B: 0.1% formicacid in acetonitrile): 0 min (90% A), 1 min (90% A), 3 min (10% A), 4min (10% A), 4.5 min (90% A), 6 min (90% A). The temperature of theTurbo V ion source is 500° C. The following MS instrument parameters areused: curtain gas 20 units (Example 1), 16 units (Example 2) or 15 units(Example 3), ion spray voltage 5 kV (Example 1/2) or 4.5 units (Example3), gas 1 35 units (Example 1/3) or 25 units (Example 2), gas 2 30units, CAD gas 4 units (Example 1/3) or 3 units (Example 2). Thesubstances are quantified by peak heights or areas using extracted ionchromatograms of specific MRM experiments.

The plasma concentration/time plots determined are used to calculate thepharmacokinetic parameters such as AUC, C_(max), MRT (mean residencetime), t_(1/2) (half life) and CL (clearance) employing the validatedpharmacokinetic calculation programs KinEx (Vers. 2.5 and 3).

As the substance quantification is carried out in plasma, it isnecessary to determine the blood/plasma distribution of the substance tobe able to adjust the pharamacokinetic parameters in an appropriatemanner To this end, a defined amount of substance is incubated inheparinized whole blood of the species in question in a rocking rollermixer for 20 min. After centrifugation at 1000 g, the plasmaconcentration is measured (see above) and determined by calculating thequotient of the c_(b)/c_(p) values.

Following intravenous administration of 0.3 mg/kg of the compoundsaccording to the invention in rats, the following values were recorded:

Example 1.* 2.** 3.** AUC_(norm) [kg · h/l] 4.36 1.79 1.36 CL_(blood)[lh/kg] 0.29 0.53 1.02 MRT [h] 4.1 2.3 2.3 t_(1/2) [h] 3.4 1.7 1.9*15-minute infusion **i.v. bolus administration

B-5. Safety Profile

The substances according to the invention show a surprisingly favourablesafety profile in vivo which was established by non-clinical safetystudies according to OECD (OECD guidelines for testing of chemicals, No.407) and ICH (3BS2A) guidelines.

C. Working Examples for Pharmaceutical Compositions

The compounds according to the invention can be converted topharmaceutical formulations as follows

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose(monohydrate), 50 mg of maize starch (native), 10 mg ofpolyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg ofmagnesium stearate.

Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm.

Preparation:

The mixture of the compound according to the invention, lactose andstarch is granulated with a 5% solution (w/w) of the PVP in water. Afterdrying, the granules are mixed with the magnesium stearate for 5minutes. This mixture is pressed with a conventional tableting press(for tablet dimensions see above). The guide value used for the pressingis a pressing force of 15 kN.

Suspension for Oral Administration:

Composition:

1000 mg of the compound according to the invention, 1000 mg of ethanol(96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and99 g of water.

A single dose of 100 mg of the compound according to the inventioncorresponds to 10 ml of oral suspension.

Preparation:

The Rhodigel is suspended in ethanol and the compound according to theinvention is added to the suspension. The water is added while stirring.The mixture is stirred for approx. 6 h until swelling of the Rhodigelhas ended.

Solution for Oral Administration:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbateand 97 g of polyethylene glycol 400. A single dose of 100 mg of thecompound according to the invention corresponds to 20 g of oralsolution.

Preparation:

The compound according to the invention is suspended in the mixture ofpolyethylene glycol and polysorbate while stirring. The stirringoperation is continued until dissolution of the compound according tothe invention is complete.

i.v. Solution:

The compound according to the invention is dissolved in a concentrationbelow the saturation solubility in a physiologically acceptable solvent(e.g. isotonic saline, glucose solution 5% and/or PEG 400 solution 30%).The solution is subjected to sterile filtration and dispensed intosterile and pyrogen-free injection vessels.

1. A compound of formula (I)

in which R¹ represents hydrogen or (C₁-C₄)-alkyl, where (C₁-C₄)-alkylmay be substituted by one or two substituents independently of oneanother selected from the group consisting of fluorine andtrifluoromethyl, and their N-oxides, salts, and salts of the N-oxides.2. The compound of the formula (I) according to claim 1 in which R¹represents hydrogen or methyl, where methyl may be substituted by atrifluoromethyl substituent, and salts thereof.
 3. The compound of theformula (I) according to claim 1, selected from the group consisting of:methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate;methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate;methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}(2,2,2-trifluoroethyl)carbamate;methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatehydrochloride; methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatesulphate; methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatephosphate; methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatemesylate; methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamateethane-1,2-disulphonate; methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatemaleate; and methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamatenitrate.
 4. A process for preparing a compound of claim 1, wherein acompound of the formula (II)

[A] is reacted in an inert solvent in the presence of hexabutyltin and asuitable palladium catalyst with intermediate formation of a tin specieswith the compound of the formula (III)

to give the compound of the formula (IV)

this is then reduced in an inert solvent with a suitable reducing agentto give the compound of the formula (V)

and this is then reacted in the presence of a suitable base in thepresence or absence of a solvent with methyl chloroformate to give thecompound of the formula (I-A)

or [B] the compound of the formula (II) is reacted in an inert solventwith copper cyanide to give the compound of the formula (VI)

this is then, under acidic conditions, converted into the compound ofthe formula (VII)

this is subsequently reacted in an inert solvent in the presence of asuitable base with the compound of the formula (VIII)

to give the compound of the formula (IX)

and this is then reduced in an inert solvent in the presence of asuitable reducing agent to give the compound (V), and this issubsequently reacted further according to process [A] to give compound(I-A), or [C] the compound of the formula (I-A) is reacted in an inertsolvent in the presence of a suitable base with a compound of theformula (X)R^(1A)-X¹ _((X)), in which R^(1A) represents (C₁-C₄)-alkyl, where(C₁-C₄)-alkyl may be substituted by one or two substituentsindependently of one another selected from the group consisting offluorine and trifluoromethyl, and X¹ represents a leaving group such as,for example, halogen, in particular bromine or iodine,trichloromethanesulphonate, mesylate or tosylate to give a compound ofthe formula (I-B)

in which R^(1A) has the meaning given above, and the resulting compoundsof the formulae (I-A) and (I-B) are, where appropriate, converted withthe appropriate (i) solvents and/or (ii) acids or bases into theirsolvates, salts and/or solvates of the salts.
 5. (canceled) 6.(canceled)
 7. (canceled)
 8. A pharmaceutical formulation comprising acompound of claim 1 and an inert, non-toxic, pharmaceutically suitableexcipient.
 9. A pharmaceutical composition comprising a compound ofclaim 1 and a further active compound selected from the group consistingof an organic nitrates, an NO donors, a cGMP-PDE inhibitors, an agentshaving antithrombotic activity, an agents for lowering blood pressure,and an agents for altering lipid metabolism.
 10. (canceled)
 11. AmMethod for the treatment and/or prophylaxis of heart failure, anginapectoris, hypertension, pulmonary hypertension, ischaemias, vasculardisorders, kidney failure, thromboembolic disorders, fibrotic disordersand arteriosclerosis comprising administering to a human or animal inneed thereof an effective amount of at least one compound of claim 1.